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Cryptococcoma of a transplanted kidney in a patient presenting with recurrent urinary tract infection: a case report

Cryptococcoma of a transplanted kidney in a patient presenting with recurrent urinary tract... Background: Cryptococcosis is an important opportunistic infection of organ transplant recipients. It is the third most common fungal infection of transplant patients and occurs especially in kidney recipients. Cryptococcus neoformans is a ubiquitous fungus which infects humans by inhalation of spores. C. gattii has more recently been recognised as a pathogen. Infection commonly is disseminated affecting mainly the central nervous system and the lungs. Cryptococcoma, a localised form of the disease, has been described in various organs. We present a unique case of a cryptococcoma in a transplanted kidney. The lesion was not seen on ultrasound or uncontrasted computerised tomography but was detected by FDG-PET/CT. Case presentation: A 30 year old woman received a deceased donor kidney transplant in 2005. Due to chronic allograft nephropathy in 2014, cyclosporine and azathioprine immunosuppression was changed to tacrolimus and mycophenolate. After rapid deterioration of renal function in 2015 due to suspected non-adherence to immunosuppressants, steroid pulses were administered. The patient developed severe recurrent bacterial urinary tract infections and demonstrated several features of severe immunosuppression. She was treated for cytomegalovirus infection and BK virus was demonstrated in the urine. In addition, Kaposi sarcoma of the stomach was diagnosed on endoscopic biopsy. A metabolically-active lesion of the kidney transplant was imaged on FDG- PET/CT scan. Biopsy of the lesion demonstrated infection with cryptococcus. Escherichia coli with the same antibiotic sensitivity spectrum as that in the urine was cultured from the biopsy. Cryptococcus was not cultured from urine at that time or from several subsequent specimens. The lesion was not detected by conventional imaging. The patient manifested no other evidence of cryptococcosis. The lesion responded poorly to treatment with fluconazole. Conclusions: This is probably the first report of a case of a cryptococcoma in a transplanted organ. FDG-PET/CT scan, which is dependent on cellular metabolism, proved useful in visualising the lesion. Clinicians should be aware of this rare presentation of cryptococcosis in organ transplant recipients. Keywords: Cryptococcosis, Cryptococcoma, FDG-PET/CT scan, Kidney transplant, Urinary tract infection, Case report Background Spores enter in the patient through the airway. In im- Cryptococcosis is a serious fungal infection which occurs munocompromised patients the disease is due to reacti- usually in immunocompromised subjects [1]. Cryptococ- vation of dormant infection in most cases [4]. The most cus neoformans fungal spores are ubiquitous and com- common manifestation of systemic cryptococosis is cen- monly originate from pigeon droppings [2], but tral nervous system disease in the form of meningo- Cryptococcus gattii has different ecological sources [3]. encephalitis, but the lungs are frequently affected [2]. A localised form of the disease, or cryptococcoma, can occur in an affected organ and has been described in un- * Correspondence: [email protected] Department of Surgery, Faculty of Health Sciences, Steve Biko Academic usual locations [5, 6]. This has long been recognised Hospital and The University of Pretoria, Private Bag X323, Arcadia, Pretoria radiologically, and cryptoccoma must be distinguished 0007, South Africa from other granulomatous infections or malignant Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Muranda et al. BMC Nephrology (2018) 19:94 Page 2 of 5 tumors [7]. Localised cryptococcal lesions usually occur mycophenolate mofetil 500 mg twice daily and prednisone in conjunction with systemic disease. We present a case 5 mg daily and viral disease remained quiescent. Late in of a cryptococcoma in a transplanted kidney in a patient 2014 and during 2015 the patient developed recurrent with no other manifestations of cryptococcosis. The pa- episodes of severe bacterial urinary tract infection which tient presented with recurrent severe bacterial urinary were accompanied by SIRS response. She was admitted to tract infection, for which the reason was obscure. The hospital on five occasions with intervals of one to performance of an 18F-fluorodeoxyglucose positron 2 months. The infections responded each time to empiric emission tomography (FDG-PET/CT) revealed a (usually amoxicillin/clavulanic acid) and/or directed (on metabolically-active lesion in the transplanted kidney in occasion switched to a carbapenem) antibiotic therapy which cryptococcosis was identified on biopsy. A crypto- for 10–14 days. Initially Klebsiella pneumoniae was coccoma in a transplanted organ has not been previously cultured from urine and blood, but on the last 3 reported. occasions Escherichia coli (E. coli) was cultured, each time with similar antibiotic sensitivity. Ultrasound of Case presentation the transplant, vesicocystourography and cystoscopy were A 30 year old woman was diagnosed with end stage non-contributory to the causation of recurrent infection renal disease which was suspected to be a complication apart from grade 2 reflux into the transplant ureter. Vari- of previous malarial illness. Haemodialysis was initiated ous prophylactic antibacterials were prescribed without in 2000 and a deceased donor kidney transplant was per- success. On each occasion of admission for sepsis the graft formed in 2005. Immunosuppression was by cyclosporin, was tender and it was decided to perform an FDG-PET/ azathioprine and prednisone, without induction therapy. CT scan. This revealed a metabolically active lesion in the The post-transplant course was stable with good renal upper pole of the transplanted kidney, suggestive of an function. The patient developed diabetes mellitus in abscess (Fig. 1a). Attempted aspiration of the lesion did 2010 and was placed on insulin. Parathyroidectomy was not yield pus after several passes, and was followed by a performed in 2011 for hyperparathyroidism. She was core needle biopsy. The biopsy yielded poor non- treated in hospital once in 2012 for a urinary tract diagnostic tissue, but a positive culture of an E. coli infection. with thesameantibioticsensitivityspectrum as that Renal function deteriorated over a period of 6 months cultivated from urine and blood. The biopsy was repeated in 2014, serum creatinine increasing from a baseline of and this time yielded diagnosable material. Routine histo- less than 100 to more than 300 μmol/l. This prompted logical sections were stained with haematoxylin and eosin the performance of a transplant biopsy. Chronic allograft and revealed renal tissue with a prominent infiltrate of nephropathy was diagnosed and immunosuppression cryptococcus round yeast bodies. The fungal elements changed to tacrolimus (target serum trough level 5- were organised into groups in a myxoid and inflammatory 7 ng/ml), mycophenolate mofetil (1 g twice daily) and background in most of the tissue. Alcian blue staining prednisone (10 mg/day). Renal function remained stable demonstrated a thick mucinous fungal capsule. The mi- until rapid deterioration occurred early in 2015 due to croscopy confirmed the presence of chronic allograft suspected non-adherence to immune suppressants dur- nephropathy. There were areas of prominent interstitial ing a foreign visit. Three steroid pulses (methylpredniso- fibrosis with atrophic tubuli and occasional sclerotic glom- lone 250 mg daily) were administered, and a repeat eruli. There were no specific features of BK virus nephrop- transplant biopsy was performed. The histological ap- athy present. The biopsies had not been specifically pearance was essentially unchanged. Renal function im- cultured for fungal pathogens as the finding was unex- proved somewhat with serum creatine decreasing from pected. At the time of discarding the plates at 48 h, there an initial value of 640 μmol/l to 395 μmol/l, and then had been no fungal growth. stabilising at a new baseline of about 380 μmol/l after On the basis of the radiological and histological ap- one further dose of methylprednisone 500 mg. Subse- pearances, a diagnosis of cryptococcoma of the trans- quently viral infection due to cytomegalo-, and BK-virus planted kidney was made. Investigation for systemic occurred at different times. The virus infections were cryptococcosis was commenced. An uncontrasted brain diagnosed by quantitative serum PCR for CMV and by and lung CT scan was normal. Cerebrospinal fluid exam- urine PCR for BK virus. CMV infection, which presented ination yielded the following: glucose 3.6 mmol/l, pro- as a febrile illness, was treated because of a sustained tein 0.29 g/l and adenosine deaminase 1.5 u/l. There viral load of 250–671 copies/ml. Treatment was by induc- were no cells present. India ink staining and cryptococ- tion with intravenous gancyclovir and maintenance with cus latex antigen test (CLAT) of the fluid were negative. oral valgancyclovir. The BK viral load in the urine was Bacterial and fungal culture were negative. The lungs 269,000 copies/ml. Immunosupression was progressively were examined clinically, and radiographically by plain reduced to a tacrolimus target trough level of 5 ng/ml, X-ray and CT scan. They were found to be normal. The Muranda et al. BMC Nephrology (2018) 19:94 Page 3 of 5 each dialysis session. The lesion in the kidney which had be- come detectable on ultrasound was apparently unchanged. The patient died soon after initiation of dialysis during admission to hospital for an episode of severe sepsis. Discussion This is the first description of a cryptococcoma occur- ring in a transplanted organ. Cryptococcoma is a specific form of cryptococcal disease manifesting his- tologically as a localised inflammatory mass containing amyriadof cryptococcus organisms [8]. Cryptococcomas occur mainly in the central nervous system and the lungs where they must be distinguished from granulomatous in- fections and tumours [9, 10]. This case of cryptococcal disease is most likely due to the effects of immunosuppression. Donor transmission is unlikely given that the disease occurred 10 years after the kidney transplant [11]. It occurred during a period of intensified immunosuppression by switching to a combin- ation of tacrolimus and mycophenolate mofetil. In addition a course of pulsed steroids had been administered 2 months before the diagnosis of the lesion in the kidney. Only candidiasis and aspergillosis are more frequent causes of fungal infection than cryptococcosis in organ transplant recipients [1]. The overall incidence of cryptococcosis is about 3% in solid organ recipients but is relatively more common in kidney recipients [1]. The majority of patients have disseminated disease affecting mainly the central nervous system and lungs, but a wide variety of organs can be individually affected. Infection Fig. 1 FDG-PET/CT scan demonstrating a metabolically active lesion occurs commonly 2 to 5 years after transplantation. in the transplanted kidney (panel a), and exacerbation on follow-up Patients taking calcineurin inhibitors are more likely to scan (panel b) have disease limited to the lungs [12]. Cryptococcus neo- formans, which occurs worldwide, is the most common serum cryptococcus latex antigen test (s-CLAT) was cause, but C. gattii which occurs mainly in the tropics negative. Multiple subsequent blood and urine speci- and subtropics, has now also been reported to cause in- mens were negative for fungal culture. fection in transplant recipients, especially in northwest The patient was treated with fluconazole 400 mg daily United Stated and British Columbia in Canada [4]. with the intention of continuing for 6 to 12 months. Severity of cryptococcosis is related to the net state of During this time the patient remained chronically ill the patient’s immunosuppression and overall survival of with nausea, anorexia and loss of weight, as well as the transplant patients is 70–80% [4]. recurrent urinary tract infections. On follow-up FDG- Cryptococcoma, as a localised form of cryptococcal dis- PET/CT scan after 2 months the cryptococcoma showed ease, is believed to occur more frequently in Cryptococcus a significant increase in size and intensity (Fig. 1b). A gas- gattii infection because the fungus secretes products that troscopy was performed for the upper gastro-intestinal inhibit the accumulation and infiltration of infected tissues symptoms. A mucosal mass was seen, biopsy of which by leukocytes [13]. This may allow localised survival and revealed Kaposi sarcoma. proliferation of organisms resulting in a mass lesion. This Throughout her protracted illness the patient remained is apparent in the histology of these lesions in which neu- unwilling to accept any reduction of the immunosuppres- trophil leukocytes are virually absent, and histiocytes are sion for fear of losing the kidney. Eventually, in light of poor predominant [8]. A negative s-CLAT test, as in this case, renal function and life-threatening infections, she acceded is ascribed to the localised nature of the lesion, in which to reduction and cessation of immunosuppressants, and the burden of organisms is relatively low [1]. was started on haemodialysis. Treatment for the cryptococ- Both solitary and disseminated cryptococcal disease have cosis was escalated by adding 200 mg of fluconazole after previously been demonstrated on FDG-PET/CT scanning Muranda et al. BMC Nephrology (2018) 19:94 Page 4 of 5 [7]. This was used in this case because ultrasound was non- rare presentation, and of the possibility in nonresponsive contributory and contrasted CT scan was contra-indicated transplant infection. because of deteriorating renal function. FDG-PET/CT, in Availability of data and materials which imaging is uniquely dependant on cellular metabol- Data sharing is not applicable to this article as no datasets were generated ism, can detect malignant, inflammatory and infectious foci or analysed during the current study. which may not be detected by other modalities. This in- Authors’ contributions cludes fungal lesions in which FDG-PET/CT scanning also AZM: Concept, management and supervision of management (nephrologist) provides information on therapeutic response [14], which of the patient, contribution to writing the text, final approval. LG: Management of the patient (nephrologist), collection of data, final approval. in this case was poor. MMS: Data collection of PET/CT scan, data analysis of the scan, partial writing Clinical exacerbation of fungal disease can occur in of the text, final approval. TL: Data collection of PET/CT scan, data analysis of immunocompromised hosts in the form of the immune the scan, partial writing of the text, final approval. VOLK: Concept, management of the patient (surgeon), research, principal writer, final reconstitution syndrome (IRS) on restoration of host approval. immunity [15]. IRS can also occur on reduction of im- munosuppression in organ transplant recipients, includ- Ethics approval and consent to participate ing some with cryptococcosis [16]. IRS is due to a The consent for the study of the patient for the purpose of publication was granted by the Research Ethics Committee of The Faculty of Health Sciences transient escalation of the inflammatory response and of The University of Pretoria, Ref Nr 297/2016. can be difficult to differentiate from progression of infec- tion. It is especially relevant in meningoencephalitis be- Consent for publication We were unable to obtain patient consent for this case report. The patient is cause of occurrence in the rigid confines of the skull. deceased and we have not been able to trace their next of kin or any family IRS seems unlikely in this case because of the prolonged members. Our case meets the criteria specified by the Committee on course of the illness in which deterioration of the in- Publication Ethics’ Code of Conduct for publication of case reports that relate to a deceased person. This has been presented to the Research Ethics flammatory mass on FDG-PET/CT scan occurred over a Committee of The Faculty of Health Sciences of The University of Pretoria period of several months. In addition, local transplant who have given signed approval that exhaustive attempts have been made manifestations of disease, such as the tenderness, were to contact the family and that the paper has been sufficiently anonymised not to cause harm to the patient’s family. probably more related to the recurrent bouts of bacterial pyelonephritis. Competing interests The major burden of illness in this patient was severe The authors declare that they have no competing interests. relapsing bacterial pyelonephritis. Several factors predis- posed to this course. Intensified immunosuppression, dia- Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in betes mellitus, and vesico-ureteric reflux were probably all published maps and institutional affiliations. contributory. Nevertheless, it seems that the fungal and bacterial infections coexisted in the kidney transplant. Author details Department of Nephrology, Steve Biko Academic Hospital and The One can speculate that the crytococcoma may have University of Pretoria, Pretoria, South Africa. Department of Nuclear been causative of recurrent pyelonephritis in this patient. Medicine, Steve Biko Academic Hospital and The University of Pretoria, The effect of cryptococcus on leukocytes described above Pretoria, South Africa. Department of Surgery, Faculty of Health Sciences, Steve Biko Academic Hospital and The University of Pretoria, Private Bag may have caused persistence of bacteria in the renal X323, Arcadia, Pretoria 0007, South Africa. tissue in and around the cryptococcoma by leukocyte ex- clusion, and would be a novel mechanism of persistence Received: 16 September 2016 Accepted: 9 April 2018 of bacterial infection. This may be the reason for culture of E. coli from the first percutaneous biopsy before the References successful core biopsy. On the other hand the mass 1. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et effect of the cryptococcoma may have impeded drainage al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin of urine from one or more calyces causing stasis and per- Infect Dis. 2010;50(8):1101–11. sistence of bacteria, and consequently recurrent bouts of 2. Baddley JW, Forrest GN, AST Infectious Diseases Community of Practice. urinary tract infection. While the proposition that the Cryptococcosis in solid organ transplantation. Am J Transplant. 2013;13:242–9. 3. Chen SCA, Meyer W, Sorrell TC. Cryptococcus gattii infections. Clin Micro cryptococcoma played a role in the relapsing bacterial in- Rev. 2014;27(4):980–1024. fection in this patient is unproven, it remains an intriguing 4. Shoham S, Marr KA. Invasive fungal infections in solid organ transplant hypothesis. recipients. Future Microbiol. 2012;7(5):639–55. 5. Lin GY, Lin TY, Lee JT, Yang FC. An isolated cryptococcoma mimicking nasopharyngeal cancer. Infection. 2015;43:129–30. 6. Kagan E, Madden MB, Parsons CH. Successful treatment of a locally invasive Conclusions cryptococcoma mimicking primary thyroid cancer with fluconazole. Am J Med Sci. 2010;340(2):173–5. In conclusion, it seems that cryptococcal infection may 7. Zhang Y, Li N, Zhang Y, Li H, Chen X, Wang S. Clinical analysis of 76 patients rarely present as a localised infection of the graft in renal pathologically diagnosed with pulmonary cryptococcosis. Eur Respir J. 2012; transplant recipients. Clinicians should be aware of this 40(5):1191–200. Muranda et al. BMC Nephrology (2018) 19:94 Page 5 of 5 8. Shibuya K, Coulson WF, Wollman JS, Wakayama M, Ando T, Oharaseki T, et al. Histopathology of cryptococcosis and other fungal infections in patients with acquired immunodeficiency syndrome. Int J Infect Dis. 2001;5(2):78–85. 9. Ulett KB, Cockburn JWJ, Jeffree R, Woods ML. Cerebral cryptococcoma mimicking glioblastoma. BMJ Case Rep. 2017; https://doi.org/10.1136/bcr- 2016-218824. 10. Gupta NC, Maloof J, Gunel E. Probability of malignancy in solitary pulmonary nodules using fluorine-18-FDG and PET. J Nucl Med. 1996;37(6): 943–8. 11. Sun H-Y, Alexander BD, Lortholary O, Dromer F, Forrest GN, Lyon GM, et al. Unrecognized pretransplant and donor-derived cryptococcal disease in organ transplant recipients. Clin Infect Dis. 2010;51(9):1062–9. 12. Singh N, Alexander BD, Lortholary O, Dromer F, Gupta KL, John GT, et al. Cryptococcus neoformans in organ transplant recipients: impact of calcineurin-inhibitor agents on mortality. J Infect Dis. 2007;195:756–64. 13. Wright L, Bubb W, Davidson J, Santangelo R, Krockenberger M, Himmelreich U, et al. Metabolites released by Cryptococcus neoformans var. neoformans and var. gattii differentially affect human neutrophil function. Microbes Infect. 2002;4(14):1427–38. 14. Ankrah AO, Sathekge MM, Dierckx RAJO, Glaudemans AWJM. Imaging fungal infections in children. Clin Transl Imaging. 2016;4:57–72. 15. Perfect JR. The impact of the host on fungal infections. Am J Med. 2012; 125(1):39–51. 16. Singh N, Lortholary O, Alexander BD, Gupta KL, John GT, Pursell K, et al. An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients. Clin Infect Dis. 2005; 40(12):1756–61. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Nephrology Springer Journals

Cryptococcoma of a transplanted kidney in a patient presenting with recurrent urinary tract infection: a case report

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Medicine & Public Health; Nephrology; Internal Medicine
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Abstract

Background: Cryptococcosis is an important opportunistic infection of organ transplant recipients. It is the third most common fungal infection of transplant patients and occurs especially in kidney recipients. Cryptococcus neoformans is a ubiquitous fungus which infects humans by inhalation of spores. C. gattii has more recently been recognised as a pathogen. Infection commonly is disseminated affecting mainly the central nervous system and the lungs. Cryptococcoma, a localised form of the disease, has been described in various organs. We present a unique case of a cryptococcoma in a transplanted kidney. The lesion was not seen on ultrasound or uncontrasted computerised tomography but was detected by FDG-PET/CT. Case presentation: A 30 year old woman received a deceased donor kidney transplant in 2005. Due to chronic allograft nephropathy in 2014, cyclosporine and azathioprine immunosuppression was changed to tacrolimus and mycophenolate. After rapid deterioration of renal function in 2015 due to suspected non-adherence to immunosuppressants, steroid pulses were administered. The patient developed severe recurrent bacterial urinary tract infections and demonstrated several features of severe immunosuppression. She was treated for cytomegalovirus infection and BK virus was demonstrated in the urine. In addition, Kaposi sarcoma of the stomach was diagnosed on endoscopic biopsy. A metabolically-active lesion of the kidney transplant was imaged on FDG- PET/CT scan. Biopsy of the lesion demonstrated infection with cryptococcus. Escherichia coli with the same antibiotic sensitivity spectrum as that in the urine was cultured from the biopsy. Cryptococcus was not cultured from urine at that time or from several subsequent specimens. The lesion was not detected by conventional imaging. The patient manifested no other evidence of cryptococcosis. The lesion responded poorly to treatment with fluconazole. Conclusions: This is probably the first report of a case of a cryptococcoma in a transplanted organ. FDG-PET/CT scan, which is dependent on cellular metabolism, proved useful in visualising the lesion. Clinicians should be aware of this rare presentation of cryptococcosis in organ transplant recipients. Keywords: Cryptococcosis, Cryptococcoma, FDG-PET/CT scan, Kidney transplant, Urinary tract infection, Case report Background Spores enter in the patient through the airway. In im- Cryptococcosis is a serious fungal infection which occurs munocompromised patients the disease is due to reacti- usually in immunocompromised subjects [1]. Cryptococ- vation of dormant infection in most cases [4]. The most cus neoformans fungal spores are ubiquitous and com- common manifestation of systemic cryptococosis is cen- monly originate from pigeon droppings [2], but tral nervous system disease in the form of meningo- Cryptococcus gattii has different ecological sources [3]. encephalitis, but the lungs are frequently affected [2]. A localised form of the disease, or cryptococcoma, can occur in an affected organ and has been described in un- * Correspondence: [email protected] Department of Surgery, Faculty of Health Sciences, Steve Biko Academic usual locations [5, 6]. This has long been recognised Hospital and The University of Pretoria, Private Bag X323, Arcadia, Pretoria radiologically, and cryptoccoma must be distinguished 0007, South Africa from other granulomatous infections or malignant Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Muranda et al. BMC Nephrology (2018) 19:94 Page 2 of 5 tumors [7]. Localised cryptococcal lesions usually occur mycophenolate mofetil 500 mg twice daily and prednisone in conjunction with systemic disease. We present a case 5 mg daily and viral disease remained quiescent. Late in of a cryptococcoma in a transplanted kidney in a patient 2014 and during 2015 the patient developed recurrent with no other manifestations of cryptococcosis. The pa- episodes of severe bacterial urinary tract infection which tient presented with recurrent severe bacterial urinary were accompanied by SIRS response. She was admitted to tract infection, for which the reason was obscure. The hospital on five occasions with intervals of one to performance of an 18F-fluorodeoxyglucose positron 2 months. The infections responded each time to empiric emission tomography (FDG-PET/CT) revealed a (usually amoxicillin/clavulanic acid) and/or directed (on metabolically-active lesion in the transplanted kidney in occasion switched to a carbapenem) antibiotic therapy which cryptococcosis was identified on biopsy. A crypto- for 10–14 days. Initially Klebsiella pneumoniae was coccoma in a transplanted organ has not been previously cultured from urine and blood, but on the last 3 reported. occasions Escherichia coli (E. coli) was cultured, each time with similar antibiotic sensitivity. Ultrasound of Case presentation the transplant, vesicocystourography and cystoscopy were A 30 year old woman was diagnosed with end stage non-contributory to the causation of recurrent infection renal disease which was suspected to be a complication apart from grade 2 reflux into the transplant ureter. Vari- of previous malarial illness. Haemodialysis was initiated ous prophylactic antibacterials were prescribed without in 2000 and a deceased donor kidney transplant was per- success. On each occasion of admission for sepsis the graft formed in 2005. Immunosuppression was by cyclosporin, was tender and it was decided to perform an FDG-PET/ azathioprine and prednisone, without induction therapy. CT scan. This revealed a metabolically active lesion in the The post-transplant course was stable with good renal upper pole of the transplanted kidney, suggestive of an function. The patient developed diabetes mellitus in abscess (Fig. 1a). Attempted aspiration of the lesion did 2010 and was placed on insulin. Parathyroidectomy was not yield pus after several passes, and was followed by a performed in 2011 for hyperparathyroidism. She was core needle biopsy. The biopsy yielded poor non- treated in hospital once in 2012 for a urinary tract diagnostic tissue, but a positive culture of an E. coli infection. with thesameantibioticsensitivityspectrum as that Renal function deteriorated over a period of 6 months cultivated from urine and blood. The biopsy was repeated in 2014, serum creatinine increasing from a baseline of and this time yielded diagnosable material. Routine histo- less than 100 to more than 300 μmol/l. This prompted logical sections were stained with haematoxylin and eosin the performance of a transplant biopsy. Chronic allograft and revealed renal tissue with a prominent infiltrate of nephropathy was diagnosed and immunosuppression cryptococcus round yeast bodies. The fungal elements changed to tacrolimus (target serum trough level 5- were organised into groups in a myxoid and inflammatory 7 ng/ml), mycophenolate mofetil (1 g twice daily) and background in most of the tissue. Alcian blue staining prednisone (10 mg/day). Renal function remained stable demonstrated a thick mucinous fungal capsule. The mi- until rapid deterioration occurred early in 2015 due to croscopy confirmed the presence of chronic allograft suspected non-adherence to immune suppressants dur- nephropathy. There were areas of prominent interstitial ing a foreign visit. Three steroid pulses (methylpredniso- fibrosis with atrophic tubuli and occasional sclerotic glom- lone 250 mg daily) were administered, and a repeat eruli. There were no specific features of BK virus nephrop- transplant biopsy was performed. The histological ap- athy present. The biopsies had not been specifically pearance was essentially unchanged. Renal function im- cultured for fungal pathogens as the finding was unex- proved somewhat with serum creatine decreasing from pected. At the time of discarding the plates at 48 h, there an initial value of 640 μmol/l to 395 μmol/l, and then had been no fungal growth. stabilising at a new baseline of about 380 μmol/l after On the basis of the radiological and histological ap- one further dose of methylprednisone 500 mg. Subse- pearances, a diagnosis of cryptococcoma of the trans- quently viral infection due to cytomegalo-, and BK-virus planted kidney was made. Investigation for systemic occurred at different times. The virus infections were cryptococcosis was commenced. An uncontrasted brain diagnosed by quantitative serum PCR for CMV and by and lung CT scan was normal. Cerebrospinal fluid exam- urine PCR for BK virus. CMV infection, which presented ination yielded the following: glucose 3.6 mmol/l, pro- as a febrile illness, was treated because of a sustained tein 0.29 g/l and adenosine deaminase 1.5 u/l. There viral load of 250–671 copies/ml. Treatment was by induc- were no cells present. India ink staining and cryptococ- tion with intravenous gancyclovir and maintenance with cus latex antigen test (CLAT) of the fluid were negative. oral valgancyclovir. The BK viral load in the urine was Bacterial and fungal culture were negative. The lungs 269,000 copies/ml. Immunosupression was progressively were examined clinically, and radiographically by plain reduced to a tacrolimus target trough level of 5 ng/ml, X-ray and CT scan. They were found to be normal. The Muranda et al. BMC Nephrology (2018) 19:94 Page 3 of 5 each dialysis session. The lesion in the kidney which had be- come detectable on ultrasound was apparently unchanged. The patient died soon after initiation of dialysis during admission to hospital for an episode of severe sepsis. Discussion This is the first description of a cryptococcoma occur- ring in a transplanted organ. Cryptococcoma is a specific form of cryptococcal disease manifesting his- tologically as a localised inflammatory mass containing amyriadof cryptococcus organisms [8]. Cryptococcomas occur mainly in the central nervous system and the lungs where they must be distinguished from granulomatous in- fections and tumours [9, 10]. This case of cryptococcal disease is most likely due to the effects of immunosuppression. Donor transmission is unlikely given that the disease occurred 10 years after the kidney transplant [11]. It occurred during a period of intensified immunosuppression by switching to a combin- ation of tacrolimus and mycophenolate mofetil. In addition a course of pulsed steroids had been administered 2 months before the diagnosis of the lesion in the kidney. Only candidiasis and aspergillosis are more frequent causes of fungal infection than cryptococcosis in organ transplant recipients [1]. The overall incidence of cryptococcosis is about 3% in solid organ recipients but is relatively more common in kidney recipients [1]. The majority of patients have disseminated disease affecting mainly the central nervous system and lungs, but a wide variety of organs can be individually affected. Infection Fig. 1 FDG-PET/CT scan demonstrating a metabolically active lesion occurs commonly 2 to 5 years after transplantation. in the transplanted kidney (panel a), and exacerbation on follow-up Patients taking calcineurin inhibitors are more likely to scan (panel b) have disease limited to the lungs [12]. Cryptococcus neo- formans, which occurs worldwide, is the most common serum cryptococcus latex antigen test (s-CLAT) was cause, but C. gattii which occurs mainly in the tropics negative. Multiple subsequent blood and urine speci- and subtropics, has now also been reported to cause in- mens were negative for fungal culture. fection in transplant recipients, especially in northwest The patient was treated with fluconazole 400 mg daily United Stated and British Columbia in Canada [4]. with the intention of continuing for 6 to 12 months. Severity of cryptococcosis is related to the net state of During this time the patient remained chronically ill the patient’s immunosuppression and overall survival of with nausea, anorexia and loss of weight, as well as the transplant patients is 70–80% [4]. recurrent urinary tract infections. On follow-up FDG- Cryptococcoma, as a localised form of cryptococcal dis- PET/CT scan after 2 months the cryptococcoma showed ease, is believed to occur more frequently in Cryptococcus a significant increase in size and intensity (Fig. 1b). A gas- gattii infection because the fungus secretes products that troscopy was performed for the upper gastro-intestinal inhibit the accumulation and infiltration of infected tissues symptoms. A mucosal mass was seen, biopsy of which by leukocytes [13]. This may allow localised survival and revealed Kaposi sarcoma. proliferation of organisms resulting in a mass lesion. This Throughout her protracted illness the patient remained is apparent in the histology of these lesions in which neu- unwilling to accept any reduction of the immunosuppres- trophil leukocytes are virually absent, and histiocytes are sion for fear of losing the kidney. Eventually, in light of poor predominant [8]. A negative s-CLAT test, as in this case, renal function and life-threatening infections, she acceded is ascribed to the localised nature of the lesion, in which to reduction and cessation of immunosuppressants, and the burden of organisms is relatively low [1]. was started on haemodialysis. Treatment for the cryptococ- Both solitary and disseminated cryptococcal disease have cosis was escalated by adding 200 mg of fluconazole after previously been demonstrated on FDG-PET/CT scanning Muranda et al. BMC Nephrology (2018) 19:94 Page 4 of 5 [7]. This was used in this case because ultrasound was non- rare presentation, and of the possibility in nonresponsive contributory and contrasted CT scan was contra-indicated transplant infection. because of deteriorating renal function. FDG-PET/CT, in Availability of data and materials which imaging is uniquely dependant on cellular metabol- Data sharing is not applicable to this article as no datasets were generated ism, can detect malignant, inflammatory and infectious foci or analysed during the current study. which may not be detected by other modalities. This in- Authors’ contributions cludes fungal lesions in which FDG-PET/CT scanning also AZM: Concept, management and supervision of management (nephrologist) provides information on therapeutic response [14], which of the patient, contribution to writing the text, final approval. LG: Management of the patient (nephrologist), collection of data, final approval. in this case was poor. MMS: Data collection of PET/CT scan, data analysis of the scan, partial writing Clinical exacerbation of fungal disease can occur in of the text, final approval. TL: Data collection of PET/CT scan, data analysis of immunocompromised hosts in the form of the immune the scan, partial writing of the text, final approval. VOLK: Concept, management of the patient (surgeon), research, principal writer, final reconstitution syndrome (IRS) on restoration of host approval. immunity [15]. IRS can also occur on reduction of im- munosuppression in organ transplant recipients, includ- Ethics approval and consent to participate ing some with cryptococcosis [16]. IRS is due to a The consent for the study of the patient for the purpose of publication was granted by the Research Ethics Committee of The Faculty of Health Sciences transient escalation of the inflammatory response and of The University of Pretoria, Ref Nr 297/2016. can be difficult to differentiate from progression of infec- tion. It is especially relevant in meningoencephalitis be- Consent for publication We were unable to obtain patient consent for this case report. The patient is cause of occurrence in the rigid confines of the skull. deceased and we have not been able to trace their next of kin or any family IRS seems unlikely in this case because of the prolonged members. Our case meets the criteria specified by the Committee on course of the illness in which deterioration of the in- Publication Ethics’ Code of Conduct for publication of case reports that relate to a deceased person. This has been presented to the Research Ethics flammatory mass on FDG-PET/CT scan occurred over a Committee of The Faculty of Health Sciences of The University of Pretoria period of several months. In addition, local transplant who have given signed approval that exhaustive attempts have been made manifestations of disease, such as the tenderness, were to contact the family and that the paper has been sufficiently anonymised not to cause harm to the patient’s family. probably more related to the recurrent bouts of bacterial pyelonephritis. Competing interests The major burden of illness in this patient was severe The authors declare that they have no competing interests. relapsing bacterial pyelonephritis. Several factors predis- posed to this course. Intensified immunosuppression, dia- Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in betes mellitus, and vesico-ureteric reflux were probably all published maps and institutional affiliations. contributory. Nevertheless, it seems that the fungal and bacterial infections coexisted in the kidney transplant. Author details Department of Nephrology, Steve Biko Academic Hospital and The One can speculate that the crytococcoma may have University of Pretoria, Pretoria, South Africa. Department of Nuclear been causative of recurrent pyelonephritis in this patient. Medicine, Steve Biko Academic Hospital and The University of Pretoria, The effect of cryptococcus on leukocytes described above Pretoria, South Africa. Department of Surgery, Faculty of Health Sciences, Steve Biko Academic Hospital and The University of Pretoria, Private Bag may have caused persistence of bacteria in the renal X323, Arcadia, Pretoria 0007, South Africa. tissue in and around the cryptococcoma by leukocyte ex- clusion, and would be a novel mechanism of persistence Received: 16 September 2016 Accepted: 9 April 2018 of bacterial infection. This may be the reason for culture of E. coli from the first percutaneous biopsy before the References successful core biopsy. On the other hand the mass 1. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et effect of the cryptococcoma may have impeded drainage al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin of urine from one or more calyces causing stasis and per- Infect Dis. 2010;50(8):1101–11. sistence of bacteria, and consequently recurrent bouts of 2. Baddley JW, Forrest GN, AST Infectious Diseases Community of Practice. urinary tract infection. While the proposition that the Cryptococcosis in solid organ transplantation. Am J Transplant. 2013;13:242–9. 3. Chen SCA, Meyer W, Sorrell TC. Cryptococcus gattii infections. Clin Micro cryptococcoma played a role in the relapsing bacterial in- Rev. 2014;27(4):980–1024. fection in this patient is unproven, it remains an intriguing 4. Shoham S, Marr KA. Invasive fungal infections in solid organ transplant hypothesis. recipients. Future Microbiol. 2012;7(5):639–55. 5. Lin GY, Lin TY, Lee JT, Yang FC. An isolated cryptococcoma mimicking nasopharyngeal cancer. Infection. 2015;43:129–30. 6. Kagan E, Madden MB, Parsons CH. Successful treatment of a locally invasive Conclusions cryptococcoma mimicking primary thyroid cancer with fluconazole. Am J Med Sci. 2010;340(2):173–5. In conclusion, it seems that cryptococcal infection may 7. Zhang Y, Li N, Zhang Y, Li H, Chen X, Wang S. Clinical analysis of 76 patients rarely present as a localised infection of the graft in renal pathologically diagnosed with pulmonary cryptococcosis. Eur Respir J. 2012; transplant recipients. Clinicians should be aware of this 40(5):1191–200. Muranda et al. BMC Nephrology (2018) 19:94 Page 5 of 5 8. Shibuya K, Coulson WF, Wollman JS, Wakayama M, Ando T, Oharaseki T, et al. Histopathology of cryptococcosis and other fungal infections in patients with acquired immunodeficiency syndrome. Int J Infect Dis. 2001;5(2):78–85. 9. Ulett KB, Cockburn JWJ, Jeffree R, Woods ML. Cerebral cryptococcoma mimicking glioblastoma. BMJ Case Rep. 2017; https://doi.org/10.1136/bcr- 2016-218824. 10. Gupta NC, Maloof J, Gunel E. Probability of malignancy in solitary pulmonary nodules using fluorine-18-FDG and PET. J Nucl Med. 1996;37(6): 943–8. 11. Sun H-Y, Alexander BD, Lortholary O, Dromer F, Forrest GN, Lyon GM, et al. Unrecognized pretransplant and donor-derived cryptococcal disease in organ transplant recipients. Clin Infect Dis. 2010;51(9):1062–9. 12. Singh N, Alexander BD, Lortholary O, Dromer F, Gupta KL, John GT, et al. Cryptococcus neoformans in organ transplant recipients: impact of calcineurin-inhibitor agents on mortality. J Infect Dis. 2007;195:756–64. 13. Wright L, Bubb W, Davidson J, Santangelo R, Krockenberger M, Himmelreich U, et al. Metabolites released by Cryptococcus neoformans var. neoformans and var. gattii differentially affect human neutrophil function. Microbes Infect. 2002;4(14):1427–38. 14. Ankrah AO, Sathekge MM, Dierckx RAJO, Glaudemans AWJM. Imaging fungal infections in children. Clin Transl Imaging. 2016;4:57–72. 15. Perfect JR. The impact of the host on fungal infections. Am J Med. 2012; 125(1):39–51. 16. Singh N, Lortholary O, Alexander BD, Gupta KL, John GT, Pursell K, et al. 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BMC Nephrology – Springer Journals

Published: Apr 23, 2018

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